a. Field of Invention
This invention relates generally to novel tertiary amino-indazole compounds, to pharmaceutical compositions containing such compounds and to processes for making them. More particularly, this invention is concerned with novel tertiary amino-indazole compounds having the following general formula: ##SPC2##
Wherein R represents a hydrogen or halogen atom; R.sub.1 represents an alkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted aralkyl group; R.sub.2 and R.sub.3 both represent a lower alkyl or aralkyl group and W represents a branched chain alkylene group and salts such as acid addition and quaternary ammonium salts thereof.
B. Prior Art
1-Substituted-3-dialkylaminoalkoxy-1H-indazole compounds of the following general formula: ##SPC3##
Wherein R, R.sub.1, R.sub.2, and R.sub.3 have the same significance as in Formula I hereinbefore, R.sub.4 represents a hydrogen atom or an alkyl group, and n is 1 or 2, have been described in the prior art, for example, U.S. Pat. No. 3,318,905 issued in 1967 to Angelini Francesco of Italy. This specification describes the preparation of such compounds by a Williamson's type synthesis similar to that described previously in the art (cf. Name Reactions in Organic Synthesis, 2nd Edition, Academic Press - 1961) and involving, in general terms, the introduction of a preformed dialkylaminoalkyl side chain into the 3-position of an oxy-indazole compound containing appropriate substituents R and R.sub.1. More specifically, as described in the aforementioned specification, the synthesis of the desired indazole compounds of the general formula II is accomplished by reacting an appropriately substituted 3-hydroxy-1H-indazole having the following general formula: ##SPC4##
Advantageously in the form of an alkali metal salt, say the sodium or potassium salt, with a halogeno-alkyl-dialkylamine compound having the following general formula: ##EQU1## wherein R, R.sub.1, R.sub.2, R.sub.3, R.sub.4, and n have the same significance as specified hereinbefore and X represents a halogen atom, typically a chlorine atom. The reaction is usually conducted by heating the reactants together in an inert solvent, say xylene or toluene. In a variant of this prior art process described, for instance, in Dutch patent application No. 68/17852 published in 1969 to Egyesult Gyogyszer, the halogen atom in the halogeno-alkyl-dialkylamine of the general formula IV may be replaced by other suitable leaving groups such, for example, as a mesyl, tosyl, phenylsulfonate or p-bromophenylsulfonate group and the process involves the reaction of the corresponding 3-hydroxy-1H-indazole in the form of its sodium salt with the .alpha.-substituted alkyl-dialkylamine.
As described in the aforementioned United States patent specification, indazole compounds embraced by the foregoing general formula II are biologically active in that some manifest analgesic, antiinflammatory and myorelaxing activity. Probably the best known of such compounds at the present time is 1-benzyl-3-[3-(dimethylamino)propoxy]-1H-indazole, commonly referred to as benzydamine, which in the form of the hydrochloride salt, is employed in chemotherapy as an analgesic, antipyretic and/or antiinflammatory agent. In this role, the benzydamine hydrochloride is asssociated in pharmaceutical compositions with pharmaceutically acceptable organic or inorganic, solid or liquid carriers. According to the process described in the aforementioned United States specification, this compound is prepared by heating the sodium salt of 1-benzyl-3-hydroxy-1H-indazole with 3-chloropropyldimethylamine in xylene as an inert solvent. Treatment of the 1benzyl-3-[3-(dimethylamino)propoxy]-1H-indazole so-obtained with ethereal hydrochloric acid yields the corresponding hydrochloride salt, with a melting point of 160.degree.C.
Whilst the tertiary amino-indazole compounds of the foregoing general formula II are known, tertiary aminoindazole compounds of the foregoing general formula I, characterized by the presence of a branched chain alkylene group bearing substituent alkyl groups attached from carbon atoms .beta. or .gamma. to the oxygen atom, are novel compounds not specifically described in or covered by the claims of the aforementioned United States patent specification, nor are they referred to elsewhere in the literature.